SORLA/SORL1, a neuronal sorting receptor implicated in Alzheimer's disease

The proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid-beta peptides in the brain has been recognized as a major pathological pathway in Alzheimer's disease (AD). Yet, the factors that control the processing of APP and their potential contribution to the common sporadic form of AD remain poorly understood. Here, we review recent findings from studies in patients and in animal models that led to the identification of a unique sorting receptor for APP in neurons, designated SORLA/SORL1, that emerges as a key player in amyloidogenic processing and as major genetic risk factor for AD

P1367Effects of levosimendan therapy in patients with severe functional mitral regurgitation and chronic heart failure undergoing mitraclip implantation: a single-centre experience

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Probing Cosmic Strings with Satellite CMB measurements

We study the problem of searching for cosmic string signal patterns in the present high resolution and high sensitivity observations of the Cosmic Microwave Background (CMB). This article discusses a technique capable of recognizing Kaiser-Stebbins effect signatures in total intensity anisotropy maps, and shows that the biggest factor that produces confusion is represented by the acoustic oscillation features of the scale comparable to the size of horizon at recombination. Simulations show that the distribution of null signals for pure Gaussian maps converges to a $\chi^2$ distribution, with detectability threshold corresponding to a string induced step signal with an amplitude of about 100 \muK which corresponds to a limit of roughly $G\mu < 1.5\times 10^{-6}$. We study the statistics of spurious detections caused by extra-Galactic and Galactic foregrounds. For diffuse Galactic foregrounds, which represents the dominant source of contamination, we derive sky masks outlining the available region of the sky where the Galactic confusion is sub-dominant, specializing our analysis to the case represented by the frequency coverage and nominal sensitivity and resolution of the Planck experiment.Comment: 14 pages, 3 figures, to be published in JCA

On the perturbative expansion of a quantum field theory around a topological sector

The idea of treating general relativistic theories in a perturbative expansion around a topological theory has been recently put forward in the quantum gravity literature. Here we investigate the viability of this idea, by applying it to conventional Yang--Mills theory on flat spacetime. We find that the expansion around the topological theory coincides with the usual expansion around the abelian theory, though the equivalence is non-trivial. In this context, the technique appears therefore to be viable, but not to bring particularly new insights. Some implications for gravity are discussed.Comment: 7 page

Low-light-level nonlinear optics with slow light

Electromagnetically induced transparency in an optically thick, cold medium creates a unique system where pulse-propagation velocities may be orders of magnitude less than $c$ and optical nonlinearities become exceedingly large. As a result, nonlinear processes may be efficient at low-light levels. Using an atomic system with three, independent channels, we demonstrate a quantum interference switch where a laser pulse with an energy density of $\sim23$ photons per $\lambda^2/(2\pi)$ causes a 1/e absorption of a second pulse.Comment: to be published in PR

The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain

Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-{beta} (A{beta}) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/A{beata} complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of A{beta} in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/A{beta} complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between A{beta} catabolism and pro-neurotrophin signaling converging on this receptor

Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling

INTRODUCTION: Apolipoprotein E (apoE) is a carrier for brain lipids and the most important genetic risk factor for Alzheimer's disease (AD). ApoE binds the receptor sortilin, which mediates uptake of apoE‐bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved. METHODS: Combining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform–specific functions for sortilin in brain lipid metabolism and AD. RESULTS: Sortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid‐based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, compromising neuronal endocannabinoid metabolism and action. DISCUSSION: We uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4

Neutrino Interferometry In Curved Spacetime

Gravitational lensing introduces the possibility of multiple (macroscopic) paths from an astrophysical neutrino source to a detector. Such a multiplicity of paths can allow for quantum mechanical interference to take place that is qualitatively different to neutrino oscillations in flat space. After an illustrative example clarifying some under-appreciated subtleties of the phase calculation, we derive the form of the quantum mechanical phase for a neutrino mass eigenstate propagating non-radially through a Schwarzschild metric. We subsequently determine the form of the interference pattern seen at a detector. We show that the neutrino signal from a supernova could exhibit the interference effects we discuss were it lensed by an object in a suitable mass range. We finally conclude, however, that -- given current neutrino detector technology -- the probability of such lensing occurring for a (neutrino-detectable) supernova is tiny in the immediate future.Comment: 25 pages, 1 .eps figure. Updated version -- with simplified notation -- accepted for publication in Phys.Rev.D. Extra author adde

Compatibility with cap-products in Tsygan's formality and homological Duflo isomorphism

In this paper we prove, with details and in full generality, that the isomorphism induced on tangent homology by the Shoikhet-Tsygan formality $L_\infty$-quasi-isomorphism for Hochschild chains is compatible with cap-products. This is a homological analog of the compatibility with cup-products of the isomorphism induced on tangent cohomology by Kontsevich formality $L_\infty$-quasi-isomorphism for Hochschild cochains. As in the cohomological situation our proof relies on a homotopy argument involving a variant of {\bf Kontsevich eye}. In particular we clarify the r\^ole played by the {\bf I-cube} introduced in \cite{CR1}. Since we treat here the case of a most possibly general Maurer-Cartan element, not forced to be a bidifferential operator, then we take this opportunity to recall the natural algebraic structures on the pair of Hochschild cochain and chain complexes of an $A_\infty$-algebra. In particular we prove that they naturally inherit the structure of an $A_\infty$-algebra with an $A_\infty$-(bi)module.Comment: The first and second Section on $B_\infty$-algebras and modules have been completely re-written, with new results; partial revision of Section 3; the proofs in Section 4 and 5 have been re-formulated in a more general context; we added Section 8 on globalisatio

Impact of intramammary inoculation of inactivated Lactobacillus rhamnosus and antibiotics on the milk microbiota of water buffalo with subclinical mastitis

Water buffalo mastitis represents a major issue in terms of animal health, cost of therapy, premature culling and decreased milk yeld. The emergence of antibiotic resistance has led to investigate strategies to avoid or reduce antibiotics\u2019 based therapies, in particular during subclinical mastitis. The use of Generally Regarded As Safe bacteria (GRAS) such as Lactobacillus rhamnosus to restore the unbalance in mammary gland microbiota could provide potential corrective measures. The aim of this study was to investigate the changes in milk microbiota after the intramammary treatment with inactivated cultures of Lactobacillus rhamnosus of mammary gland quarters naturally affected by subclinical mastitis as compared to antibiotic therapy.A number of 43 quarters affected by subclinical mastitis with no signs of clinical inflammation and aerobic culture positive for pathogens were included in the study. The experimental design was as follows: 11 quarters were treated with antibiotics, 15 with inactivated cultures of Lactobacillus rhmnosus and 17 with PBS as negative control, by means of intrammary injection. Samples were collected at eight time points, pre- (T-29, T-21, T-15, T-7, T0 days) and post- treatment (T1, T2, and T6 days). Microbiological culture and Somatic Cell Count (SCC) were perfomed on all the samples, and microbiota was determined on milk samples collected at T0 and T6 by amplifying the V4 region of 16S rRNA gene by PCR and sequencing using next generation sequencing technique. Treatment with Lactobacillus rhamnosus elicited a strong chemotactic response, as determined by a significant increase of leukocytes in milk, but did not change the microbiological culture results of the treated quarters. For what concerns the analysis of the microbiota, the treatment with Lactobacillus rhamnosus induced the modification in relative abundance of some genera such as Pseudomonas and 5-7N15. As expected, antibiotic treatment caused major changes in microbiota structure with an increase of Methylobacterium relative abundance. No changes were detected after PBS treatment. In conclusion, the present findings demonstrated that the in vivo intrammmary treatment with Lactobacillus rhamnosus has a transient pro-inflammatory activity by increasing SCC and is capable to modify the microbiota of milk after six days from inoculation, albeit slightly, even when the bacterial cultures were heat inactivated. Further studies are necessary to assess the potential use of this GRAS as supportive therapy against mastitis